Courtat et al., J. Organometallic Chem., 145: (1978) 343-357, teach the opening of chlorine-bridged dimers of the formula [Pt(II)LCl.sub.2 ], where L is pyridine, piperidine, p-methoxyaniline, methyl-2-pyridine, methyl-4-pyridine, and trimethyl-2,4,6-pyridine with ligands such as olefins, nitriles, dimethylsulfoxide, dimethylsulfide, dimethylformamide, as well as by the use of vinyl-4-pyridine and allyl amine to provide both cis and trans compounds. There is no teaching of iodo compounds.
Braddock et al., Chem-Biol. Interactions, 11: (1975) 145-161, teach inter alia mixed ligands of the cis-[PtLL'Cl.sub.2 ] type where the mixed ligands are ammonia, paired with ethyleneimine, ethylamine, cyclopentylamine, and dimethylsulfoxide, as well as cyclohexylamine paired with dimethylsulfoxide and dimethylsulfide.
Chatt et al., J. Chem. Soc., (1955) 2787-93, describe methods for preparing binuclear platinum chloride complexes of the type [L.sub.2 Pt.sub.2 Cl.sub.4 ]. The reference teaches the sometime formation of [Pt.sub.2 LL'Cl.sub.2 ] from the dimer. The preparation of one iodine bridged complex was reported, but the ligand is apparently not amine.
Chatt et al., J. Chem. Soc., (1955) 3858-64 describe the reaction of amines with the bridged dimers [Pt.sub.2 LX.sub.2 ].sub.2 where the halogen is usually chlorine. The preparation of the mixed ligand compounds trans-[Pt(tripropylphosphine)(NH.sub.3)I.sub.2 ] and trans-[Pt(tripropylphosphine)(piperidine)I.sub.2 ] are reported, apparently prepared by reacting the corresponding dichloride in acetone with potassium iodide and then an amine. The reaction is reported as difficult, with the apparent formation of [pt(tripropylphosphine)I.sub.2 ].sub.2.
Dhara, Indian J. Chem. 8: (1970) 193-4, describes the preparation of cis-[PtL.sub.2 I.sub.2 ] which method is the method of choice for preparing the starting compounds employed in this invention.
Cleare et al., Platinum Met. Rev., 17: (1973) 2-13 describe Dhara's reaction (supra) as a general method for preparing cis-[PtL.sub.2 I.sub.2 ] and teach that these compounds react with silver nitrate and an appropriate anion to produce other cis-[PtL.sub.2 X.sub.2 ] or [PtL.sub.2 Y] species which X is a monodentate ligand and Y is a bidentate ligand. The reference does not discuss compounds where L.noteq.L'.
Cleare et al., Bioinorganic Chemistry, 2: (1973) 187-210, describe various platinum II complexes and confirm that the method of Dhara (supra) is general to provide cis-[PtL.sub.2 I.sub.2 ]. No species where L.noteq.L' are discussed.
Chatt, J. Chem. Soc., (1951) 652-658, describes halogen-bridged Pt compounds where the ligand is coordinated through P, As and Sb.
Braddock et al., Inorganic Chemistry, 13: (1974) 1170-1175 describe cis-[Pt(amine)(DMSO)Cl.sub.2 ] complexes.
U.K. patent application No. 2,060,615 is directed to platinum compounds which encompass cis-[Pt(aliphatic amine)(NH.sub.3)(halogen).sub.2 ]. Only chloro compounds are specifically taught, with very low yields (less than 10%).
U.S. Pat. No. 4,119,653 and U.S. Pat. No. 4,182,724 inter alia teach cis-[Pt(n-propylamine).sub.2 I.sub.2 ] and reaction with AgNO.sub.3 with conversion to the Cl.sub.2 species. The reference encompasses dissimilar amine ligands but does not teach their preparation.
U.S. Pat. No. 4,225,529 inter alia encompasses dissimilar amine ligands; and specifically describes cis-[Pt(amine).sub.2 I.sub.2 ] compounds and their reaction with AgNO.sub.3 to replace I.sub.2 with other ligands.
U.S. Pat. No. 3,892,790 inter alia encompasses dissimilar amine ligands; and specifically describes cis-[Pt(alicyclic amine).sub.2 Cl.sub.2 ] compounds.
The following patents also show various Pt(II) amine ligand complexes: U.S. Pat. Nos. 4,200,583; 4,140,707; 4,119,654; 4,115,418; 3,904,663; and 4,230,631.
It is noted that several of the above references discuss the antitumor effects of various platinum complexes and significant evaluation of various platinum compounds as antitumor agents is ongoing in the art.
Various Pt(II) complexes have been shown in the art to have antitumor activity. While various cis-[PtLL'X.sub.2 ] compounds, where L.noteq.L', have been broadly or generically taught, or even claimed in the patent art, very few of these compounds have been prepared, and the art related to those few preparations show low yields and/or mixed isomer products. Many of the references which generically encompass the mixed ligand compounds give no method for their preparation.
The preparation of mixed ligands cis-PtII complexes is desirable to evaluate these compounds as to their biological activity. It has now been found that cis-PtII complexes, preferably having mixed ligands, can be prepared through reaction of an oligomer, [PtLI.sub.2 ].sub.x, in a manner such that the cis-ligand compound cis-[PtLL'I.sub.2 ] is formed in high yield with no trans-isomer formation.